Hematology

Leukocyte adhesion deficiency, type 1

Leukocyte adhesion deficiency, type 1

What every physician needs to know:

Leukocyte adhesion deficiency type 1 (LAD-1) is a rare autosomal recessive disorder of leukocyte function due to mutations in the gene for the common chain (CD18) of the ß2 integrin family, critical for firm adhesion of white blood cells to the endothelial membrane.

It is characterized by delayed separation of the umbilical cord, recurrent soft tissue infections, chronic periodontitis, marked leukocytosis with a neutrophil count ranging from 12,000 to 100,000cells/mm and a high mortality rate at an early age.

The clinical phenotype is variable and is related to the severity of the reduction in ß2 integrin expression. Patients with LAD-1 with a moderate phenotype generally respond to prompt use of antibiotics during active infections; prophylactic antibiotics may reduce the risk of infection. Those with a severe phenotype generally succumb to infection by 2 years of age without definitive intervention.

The only definitive cure is allogeneic stem cell transplant.

Are you sure your patient has leukocyte adhesion deficiency, type 1? What should you expect to find?

Beware of other conditions that can mimic leukocyte adhesion deficiency, type 1:

The differential diagnosis for neutrophilia includes the following

Marrow storage pool shift (inflammation/infection)

– Acute neutrophilia from a leukemoid reaction due to the release of neutrophils from the marrow storage pool, due to inflammation and/or infection. Increased numbers of neutrophil bands are usually observed.

Pseudoneutrophilia (stress demargination)

– Acute temporary neutrophilia as a response caused by a shift of cells from the marginal to the circulating pool, secondary to vigorous exercise or acute physical or emotional stress. Neutrophil counts may be doubled, but lymphocytes and monocytes are generally unaffected by demargination.

– Leukocyte adhesion deficiency- type II (LAD-II) is similar to LAD-I as it presents with neutrophilia but results from a defect in fucose metabolism causing the absence of Sialyl Lewis X and other fucosylated ligands for the selectins. It is extremely rare and is associated with the Bombay Blood group and mental retardation.

Leukocyte adhesion deficiency type III

– Leukocyte adhesion deficiency- type III (LAD-III) is similar to LAD-I as it presents with neutrophilia and is due to a defect in integrin activation affecting both neutrophils and platelets. It is extremely rare and is also associated with a bleeding phenotype.

Transient myeloproliferative disorder

– Leukocytosis with circulating blasts found in infants with Down syndrome or mosaicism for trisomy 21 is associated with GATA-binding factor 1 (GATA1) mutation. Infants often also have hepatosplenomegaly. Median age of presentation is 3 to 7 days with the majority of cases diagnosed prior to age 2 months. Self-resolves by 3 to 6 months in most cases; however, symptomatic infants may require cytarabine.

The differential diagnosis for delayed umbilical separation includes the following

Physiologic umbilical separation

– A well infant with delayed separation of the umbilical cord and normal blood counts is extremely unlikely to have LAD-I. The mean time of umbilical cord separation is 13.9 days; however, normal infants are documented to have cord separation from 3 to 45 days.

Urachal cyst

Which individuals are most at risk for developing leukocyte adhesion deficiency, type 1:

As LAD-1 is a genetic disease with autosomal recessive inheritance, patients with a family history of the disease and/or consanguineous unions are most at risk. Both genders are equally affected.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Complete blood count with differential.

In both stimulated and unstimulated neutrophils, flow cytometry using monoclonal antibodies for CD11b and CD18 expression, to confirm absence or low-level expression of both the alpha and ß subunits of the ß2- integrin complex.

Assessment of neutrophil and monocyte adherence and aggregation.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of leukocyte adhesion deficiency, type 1?

Imaging studies do not play a significant role in diagnosing LAD-I, although directed imaging studies may serve to characterize/confirm suspected infections and an abdominal ultrasound may be useful to rule out an urachal cyst.

If you decide the patient has leukocyte adhesion deficiency, type 1, what therapies should you initiate immediately?

Antibiotics directed at any active infections should be initiated immediately. Remember that LAD-I patients are most susceptible to Staphylococcus aureus and gram-negative rods; however, fungal infections do occur. Granulocyte infusions may be life-saving; however, their use is often limited due to limited supply and to immune reactions to the allogeneic granulocytes.

More definitive therapies?

The only definitive treatment for LAD-I patients is allogeneic stem cell transplantation. For LAD-I patients with severe disease (CD18 expression less than 1%), stem cell transplant with the best available match is the recommended first line treatment. LAD-I patients with moderate disease (CD18 expression 2.5 to 10%), often respond to conservative therapy with prompt antibiotic use for active infections and prophylactic antibiotics; however, they still have a significant risk of death from overwhelming infection and stem cell transplantation should be considered on an individual basis.

What other therapies are helpful for reducing complications?

Regular dental care and maintenance of oral hygiene with the use of antimicrobial oral rinses is helpful for reducing complications. Additionally, patients should be maintained on prophylactic bactrim.

What should you tell the patient and the family about prognosis?

Without definitive intervention, LAD-I patients with severe disease generally die from overwhelming infection by 2 years of age. The goal of therapy is to minimize infections. LAD-I patients also develop keloids and have problems forming scar tissue because of defective monocyte function. Prenatal diagnosis of LAD-I can be established in families in which the mutation of the two CD18 alleles are known.

What if scenarios.

What if the patient has a fever?

For temperatures greater than 38.3°C, LAD-I patients should be urgently evaluated by a physician. Blood cultures and urine cultures should be obtained. Broad-spectrum antibiotics should be initiated and ultimately tailored if a specific organism is identified. Additional workup should be dictated by the patients presenting symptoms.

Pathophysiology

LAD-I is due to defective migration of neutrophils from the blood stream to the site of active infection. Specifically, LAD-I is caused by a defect in the common ß2 integrin chain. As a consequence, neutrophils cannot firmly attach to the endothelium or undergo transendothelial migration into tissue, thereby resulting in neutrophilia.

What other clinical manifestations may help me to diagnose leukocyte adhesion deficiency, type 1?

Most patients with LAD-I have recurrent infections, particularly soft-tissue infections. It is important to ask about umbilical cord separation, omphalitis, oral ulcers, gingivitis, and skin infections, as well as the absence of pus despite significant infection.

What other additional laboratory studies may be ordered?

No additional laboratory studies are routinely required.

What’s the evidence?

Etzioni, A. “Defects in the Leukocyte Adhesion Cascade”. Clinic Rev Allerg Immunol. vol. 38. 2010. pp. 54-60. [This is an informative review article documenting mechanisms by which leukocytes interact with endothelial cells in different congenital disorders. The crucial role of the beta 2 integrin subfamily in leukocyte emigration became established after a discovery of leukocyte adhesion deficiency 1. LAD II disorder clarified the role of the selectin receptors and their fucolsylated ligands. Patients with LAD II have less severe forms of infectious episodes and appear like the moderate phenotype of LAD 1. LAD III disorder documents the importance of the integrin-activation phase in the adhesion cascade. The various genetic abnormities leading to all adhesion molecular syndromes are detailed in this review.]

Etzioni, A, Frydman, M, Pollack, S. “Recurrent severe infections caused by a novel leukocyte adhesion deficiency”. New Engl J Med. vol. 327. 1992. pp. 1789-1792. [The authors describe two children of Arab origin who suffer from recurrent infections. Both children had severe mental retardation, short stature, distinctive facial appearance, and exhibited the Bombay phenotype. Both children had neutrophila and normal beta 2 integrin expression. The report documented a nearly complete deficiency of Sialyl-Lewis X expression on leukocytes, leading to a functional defect in neutrophil rolling on endothelial cells.]

Kuijpers, TW, van, Lier, Hamann, D. “Leukocyte adhesion deficiency type 1 (LAD-I) /variant. A novel immunodeficiency syndrome characterized by dysfunctional ß2 integrins”. J Clin Invest. vol. 100. 1997. pp. 1725-1733. [The authors were the first to describe a disorder consisting of two major hallmarks. The first a moderate leukocyte deficiency similar to that seen in LAD-1 patients and the second, a severe Glanzmann-like bleeding tendency. The authors ascribe the defect seen in both the leukocytes and platelets to an activation abnormality regulating inside-out signaling from the membrane bound integrins.]

Roy, A, Roberts, I, Norton, A, Vyas, P. “Acute megokaryoblastic leukaemia (AMKL) and transient myeloproliferative disorder (TMD) in Down syndrome: a multi-step model of myeloid leukaemnogenesis”. Br J Haematol. vol. 147. 2009. pp. 3-12. [Often infants with Down syndrome present with leukocytosis. The leukocytosis may be part of a myeloproliferative disorder which can progress into acute megakaryoblastic leukemia. The review focuses on recent studies describing clinical, hematological, and biological features of these two distinctive disorders seen in Down syndrome.]

Novack, AH, Mueller, B, Ochs, H. “Umbilical cord separation in the normal newborn”. Am J Dis Child. vol. 142. 1988. pp. 220-223. [One of the features of LAD-1 is delayed umbilical cord separation. This article points out that normal cord separation occurs between 3 to 45 days with a mean of 13.9 days.]

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